Tissue vascular supply is tightly coupled to its oxidative capacity. This is especially evident in skeletal muscle beds, each enriched in either oxidative slow-twitch or glycolytic fast-twitch myofibers (Fluck and Hoppeler, 2003; Pette and Staron, 2000). Slow-twitch muscles are characterized by high mitochondrial content, fatigue resistant (type I) fibers and dense vascularity to ensure a steady and prolonged supply of oxygen and nutrients (Annex et al., 1998; Cherwek et al., 2000; Ripoll et al., 1979). Fast-twitch (type II) muscles generally have lower oxidative capacity, a reduced blood supply and are fatigue sensitive. How the type I vs. the type II muscle vasculature is specified to match oxidative capacity is unclear.
Previous studies established that nuclear receptors such as PPARα, PPARδ and ERRα along with co-regulators PGCα1α, PGC1β and Rip140 control diverse aspects of aerobic respiration including fatty acid oxidation, oxidative phosphorylation and mitochondrial biogenesis in skeletal muscle (Arany et al., 2007; Huss et al., 2004; Lin et al., 2002; Minnich et al., 2001; Muoio et al., 2002; Seth et al., 2007; Wang et al., 2004). While signaling factors such as TGFβ1, platelet-derived growth factor, fibroblast growth factor (FGF) 1 and 2, and vascular endothelial growth factor (VEGF) are known to stimulate angiogenesis (Carmeliet, 2000; Ferrara and Kerbel, 2005; Gustafsson and Kraus, 2001), whether and how these factors orchestrate dense vascularization of aerobic muscles is unclear. One possibility is vascular arborization by co-activator PGC1 α that is induced by hypoxia and exercise (Arany et al., 2008). However, PGC1α knockout mice are viable, still retain oxidative muscle, and have normal vasculature (Arany et al., 2008; (Lin et al., 2004). Since the intrinsic enrichment of blood flow to aerobic muscles in the absence of exercise is unlikely to depend on PGC1α induction, we speculate the existence of a novel regulatory angiogenic pathway.
Estrogen receptor-related receptor γ (ERRγ), like other members of the ERR subfamily, is a constitutively active orphan nuclear receptor, though unlike ERRα and β, it is more selectively expressed in metabolically active and highly vascularized tissues such as heart, kidney, brain and skeletal muscles (Giguere, 2008; Heard et al., 2000; Hong et al., 1999). In vitro data indicate that ERRγ activates genes such as PDK4 and MCAD that play a regulatory role in oxidative fat metabolism (Huss et al., 2002; Zhang et al., 2006). Furthermore, a comprehensive gene expression analysis identified ERRγ as a key regulator of multiple genes linked to both fatty acid oxidation and mitochondrial biogenesis in cardiac muscles (Alaynick et al., 2007; Dufour et al., 2007). Expression of ERRγ is also induced in variety of tumors with hyper-metabolic demands and abundant vasculature (Ariazi et al., 2002; Cheung et al., 2005; Gao et al., 2006).